EP0904072A1 - Verfahren zur behandlung von immuno-pathologien unter verwendung mehrfach ungesättigter fetzäuren - Google Patents

Verfahren zur behandlung von immuno-pathologien unter verwendung mehrfach ungesättigter fetzäuren

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Publication number
EP0904072A1
EP0904072A1 EP97916266A EP97916266A EP0904072A1 EP 0904072 A1 EP0904072 A1 EP 0904072A1 EP 97916266 A EP97916266 A EP 97916266A EP 97916266 A EP97916266 A EP 97916266A EP 0904072 A1 EP0904072 A1 EP 0904072A1
Authority
EP
European Patent Office
Prior art keywords
acid
polyunsaturated fatty
oxa
fatty acid
double bonds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP97916266A
Other languages
English (en)
French (fr)
Other versions
EP0904072A4 (de
Inventor
Antonio Ferrante
Alfred Poulos
Michael Joseph Pitt
Christopher John Easton
Merilyn Joy Sleigh
Deborah Ann Rathjen
Fred Widmer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Children Youth and Womens Health Service Inc
Teva Pharmaceuticals Australia Pty Ltd
Original Assignee
Womens and Childrens Hospital Adelaide
Peptide Technology Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AUPN9250A external-priority patent/AUPN925096A0/en
Priority claimed from AUPN9538A external-priority patent/AUPN953896A0/en
Application filed by Womens and Childrens Hospital Adelaide, Peptide Technology Ltd filed Critical Womens and Childrens Hospital Adelaide
Publication of EP0904072A1 publication Critical patent/EP0904072A1/de
Publication of EP0904072A4 publication Critical patent/EP0904072A4/de
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to methods of treatment of a variety of disease states involving the use of new polyunsaturated fatty acids which include at least one ⁇ oxa, ⁇ thia, ⁇ oxa or ⁇ thia substitution and/or which includes an amino acid.
  • the disease states include multiple sclerosis, rheumatoid conditions, and other T-cell mediated diseases; allergic conditions such as asthma, allergic rhinitis, contact hypersensitivity; transplant rejection and graft vs. host disease and conditions where arachidonic acid metabolites are formed.
  • MS Multiple sclerosis
  • the early development of the plaque is characterised by the development of perivascular inflammation followed by the migration of lymphocytes, plasma cells and macrophages into the lesion. This is followed by astrocyte gliosis and the attempts of demyelination by oligodendrocytes. The plaque is surrounded by lymphocytes.
  • Lymphocyte reactivity against two neuronal antigens, myelin basic protein and proteolipid has been demonstrated. Although not proven, this activity would form the basis for an auto-immune response against neuronal tissue.
  • Myelopathy a disorder of the spinal cord, can have many different aetiologies, most of which are mediated by inflammation, including the following:-
  • Neurosyphillis b 12 or folate deficiency; sarcoidosis; transverse myelitis; arachidonitis; cervical spondylitis; motor neuron disease; neurofibromatosis ; spinal cord compression from tumour, disc or arthritis; lupus erythematosus of the spinal cord; and viral encephalomyelitis
  • Chronic inflammation or, as more commonly known, chronic immune system activation occurs in response to persistent antigen whose origin may be exogenous or may result from an auto-immune state. Such chronic inflammation results in local tissue destruction and depending upon the type of inflammation can result in systemic effects due to the sustained production of inflammatory mediators.
  • inflammatory mediators include the cytokines which are soluble mediators produced by activated lymphocytes and macrophages and effect cellular communication and physiological response.
  • Chronic immune activation can occur as a result of infectious disease, such as chronic fatigue syndrome or toxic shock syndrome or through auto-immune mechanisms resulting in such conditions as rheumatoid arthritis, inflammatory bowel disease, Crohns Disease and other diseases such as graft versus host disease.
  • Rheumatoid arthritis (Marrow et al, I “Auto-immune Rheumatic Disease", Blackwell Scientific Publ. Oxford, UK, Chapter 4 ppl48-207 (1987) is a disease characterised by chronic inflammation and erosion of joints that may affect up to 3% of the population, including children. Symptoms of rheumatoid arthritis include morning stiffness, swelling and pain upon motion in at lease one joint and joint swelling. Non-specific symptoms including lethargy, anorexia and weakness as well as fever and lymphadenopathy (characteristic of immune activation) may antedate joint involvement.
  • Extra-articular manifestations of rheumatoid arthritis include vasculitis, cataracts, uveitis, interstitial fibrosis, pericarditis and myocarditis, peripheral neuropathy, myeloid deposits, chronic anaemia and subcutaneous and pulmonary nodules.
  • SLE systemic lupus erythematosus
  • B cell hyper-reactivity and production of auto-antibodies is an attributed imbalance between CD8 and CD4 T cells and altered cytokine production including increased production of interleukin 1, interleukin 2 and interferon ⁇ .
  • Azathioprine is commonly used in management of the disease.
  • Systemic sclerosis scleroderma
  • the skin thickening of scleroderma is due to the accumulation of collagen in the lower dermis.
  • the immobility of the skin is caused by replacement of the subcutaneous tissue with fibrous bands.
  • Dermal fibroblasts obtained from involved skin accumulated types I, III and IV collagen, fibronectin and glycosaminoglycan. This is a secondary response to factors released by other cells. T-helper cells are demonstrable in involved skin.
  • Elevated levels of serum IL-2 and IL-2 receptor are present and correlate with clinical progression of the disease (Kahaleh et al, 1989. Ann. Item. Med. 110:446). This suggests a role for lymphokines that either stimulate collagen biosynthesis in fibroblasts or stimulate other cells such as monocytes or mast cells to produce such factors. Human chronic graft vs host disease is associated with a similar dermal fibrotic change. Interferon ⁇ is known to stimulate collagen accumulation by systemic scleroderma fibroblasts.
  • Polymyositis is a chronic inflammatory disease of skeletal muscle, characterised by symmetric weakness of proximal limb girdle muscles and muscles of the trunk, neck and pharynx. A characteristic rash may also be present (Hochberg et al, 1986, Semin Arthritis Rheum 15 :168).
  • Peripheral blood lymphocytes from patients with polymyositis produce lymphokines cytotoxic to foetal muscle cells in vitro. In addition, the proportion of activated lymphocytes is increased particularly in muscle tissue.
  • Environmental factors, particularly infectious agents influenza Bl, cocksackie virus B. Toxoplasma gondii
  • Many drugs have been implicated in chronic inflammatory myopathy, including D-penicillamine, colchanicine, and ethanol.
  • Leukoclastic vasculitis (Laken and Smiley, 1981, Dis Mon. 64:181) is the name given to the pathologic lesions seen in the blood vessels that produce palpable purpura. It is thought that the lesions are produced by the interaction of cells and humoral products.
  • the putative antigen (arising from streptococcal infection or drug interaction ) reacts with IgE attached to the surface of mast cells.
  • the activated mast cells release factors (PAF, prostaglandins, leukotrienes) causing activation of platelets and release of vasoactive amines responsible for dilation and oedema in post capillary venules.
  • Panniculitis there is also inflammation of fatty tissue.
  • septal and lobar There are two types of Panniculitis, septal and lobar.
  • Behscets Disease may be a cause of erythema nodosum.
  • Inflammatory bowel disease (IBD) and Crohns disease are chronic inflammatory conditions that fulfil some of the criteria of an auto-immune disease (Snook, Gut 31 961-963 (1991)). Inflammation and tissue damage involves the recruitment and activation of neutrophils, macrophages and lymphocytes (MacDermott et al, Adv. Immunol. 42 285-328 (1988)) which generate cytokines and proinflammatory molecules such as prostaglandins and leukotrienes (MacDermott, Mt. Sinai J. Med. 57 273-278 (1990)). As a result of chronic activation of immunocompetent cells, IL-1, IL-6 (Starter, Immunol. Res.
  • Drugs used to treat IBD and Crohns Disease include anti- inflammatory agents such as sulphasalazine (5-ASA) corticosteroids, cyclosporin A and azathiprine (Hanauer, Scand, J, Gastroenterol. 25 (Supl. 175) 97-106 (1990); Peppercorn, Annal. Intern. Med. 112 50-60 (1990)).
  • anti-CD4 and anti-TNF monoclonal antibodies have been used to successfully treat ulcerative colitis (Emmerich et al, Lancet 338 570- 571 (1991)).
  • Transplanted organs and tissues may be rejected when host T cells come in contact with donor HLA molecules.
  • the process of rejection involves several effector mechanisms including cytotoxic T cells, lymphokines (principally TNF ⁇ , IL-1, IL-2 and interferon ⁇ ) and other soluble mediators of inflammation (eg prostaglandins and leukotrienes).
  • Immunosuppressive drugs eg azathrioprine, cortocisteroids, cyclosporine A, FK506, and polyclonal and monoclonal antibodies
  • an immunocompetent graft (such as bone marrow or intestinal tissue) may react against the host resulting in graft-versus-host disease. These reactions are mediated by allogenic responses directed against a foreign MHC molecule and are mimicked in vitro by the mixed lymphocyte reaction (MLR). Graft/host interactions result in chronic inflammation surrounding the grafted tissue with an increase in markers of immune activation such as are seen in AIDS (Grant, Immunol. Today 12 171-172 (1991)).
  • Treatment of the graft/host interactions currently include either azathioprine, cyclosporin A or methylprednisone and, more recently, rapamycin (Spekowski et al, Transplantation 53 258-264 (1992); Huber et al, Bibliotheca Cardiologica. 43 103-110 (1988)).
  • Monoclonal antibodies specific for CD3 Wang et al, Clin Exp Immunol. 83 333-337 (1991)
  • CD4 Reinke et al, Lancet 338 702-703 (1991)
  • TNF ⁇ have been used experimentally to inhibit graft/host reactions.
  • Immediate hypersensitivity occurs after the binding of antigen to preformed antibodies of the IgE isotype bound to Fc receptors in mast cells or basophils. This binding leads to rapid degranulation and release of inflammatory mediators that act on tissues.
  • the production of IgE is stimulated by T lymphocytes and their products (cytokines), mainly by interleukin 4 in synergy with interleukin 5, together with interleukin 6 and TNF produced by macrophages.
  • Asthma triggered by inhalant allergens, is an IgE mediated disease.
  • Allergic rhinitis is an IgE-mediated inflammatory disease involving the nasal membranes.
  • mast cells release histamine, leukotrienes such as LTB 4 , C 4 , D 4 and E 4 , prostaglandin D 2 and proteases which are thought to be responsible for the immunopathology including an inflammatory infiltrate comprised largely of eosinophils.
  • leukotrienes such as LTB 4 , C 4 , D 4 and E 4
  • prostaglandin D 2 and proteases which are thought to be responsible for the immunopathology including an inflammatory infiltrate comprised largely of eosinophils.
  • the presence of large numbers of neutrophils are also characteristic of asthmatic tissue.
  • atopic dermatitis Although the pathogenesis of atopic dermatitis is poorly understood, the frequent co-incidence of atopic dermatitis and allergic rhinitis or asthma suggests an immediate hypersensitivity ma' v e involved. Serum IgE levels are frequently elevated in patients with ato dermatitis and often decrease during periods of remission. Topical corticosieroid preparations are used during acute episodes and may be needed chronically in some patients. As a consequence, during exacerbations of eczema, patients frequently develop secondary bacterial infections. Allergic contact dermatitis is a clinically important example of a delayed type hypersensitivity reaction which is T cell mediated involving release of T cell derived cytokines and proliferation of T cells within the skin.
  • inflammatory cells are also recruited to the involved area by cytokines and chemoattractants.
  • Frequent contact sensitisers include Rhus antigen (found in poison ivy and oak), parapheylenediamine, nickel, rubber compounds, ethylenediamine, certain local anaesthetics (eg benzocaine), chromate and neomycin.
  • Rhus antigen found in poison ivy and oak
  • parapheylenediamine nickel
  • rubber compounds ethylenediamine
  • chromate chromate
  • neomycin neomycin
  • Psoriasis (Anderson and Voorhees, Psoriasis, In; Thiers, Dobson eds. Pathogenesis of skin disease. New York. Churchill Livingstone, 1986: 67) is a primary disease of the skin characterised by well demarcated, inflammatory papules and plaques, which are typically covered by thickened scales. Neutrophils are found in psoriatic lesions. It is likely that arachidonic acid, levels of which are much higher than normal in psoriatic plaques, and its metabolites are important in this aspect of the disease.
  • drugs which block the cyclo-oxygenase pathway of arachidonic acid metabolism eg non-steroidal anti-inflammatory drugs such as indomethacin, phenylbutazone, meclotenamate
  • induce exacerbations of psoriasis eg non-steroidal anti-inflammatory drugs such as indomethacin, phenylbutazone, meclotenamate.
  • cyclosporin A Dramatic clearing of recalcitrant, severe psoriasis has been achieved using cyclosporin A.
  • the major mechanism of action of cylcosporin A is to inhibit the release of lymphokines produced by activated T lymphocytes.
  • the activated T cells in response to autologous or exogenous antigens, release factors that directly result in inflammation and epidermal proliferation, or indirectly produce these effects by activating macrophages or keratinocytes which then release cytokines, mediators of inflammation or growth factors that can elicit the pathology of psoriatic plaques.
  • Inflammation may be caused by bacteria, viruses and /or other infective agents, opportunistic infections (which may be consequent on an immunodepressed state, for example resulting from cancer or therapy, particularly cytotoxic drug therapy or radiotherapy), auto-immunity or otherwise.
  • Septic shock is an illustration of a disease involving inflammation. Many of the clinical features of Gram-negative septic shock may be reproduced in animals by the administration of LPS to animals can prompt severe metabolic and physiological changes which can lead to death.
  • LPS Associated with the injection of LPS is the extensive production of pro- inflammatory cytokines such as tumour necrosis factor alpha (TNF ⁇ ).
  • TNF ⁇ tumour necrosis factor alpha
  • Cachexia which is characteristic of chronic exposure to TNF or interleukin- 6, is a common symptom of advanced malignancy and severe infection.
  • TNF IL-1 TNF IL-1
  • mice, rats and/or humans cause anorexia, weight loss and depletion of body lipid and protein within 7 to 10 days (Cerami et al, 1985, Immunol. Lett. 11, 173: Fong et al, 1989 J. Exp. Med. 170, 1627. Moldawer et al, Am. J. Physiol., 254 G450-G456, 1988; Fong et am, Am. J Physiol. 256, R659-R665 (1989); McCarthy et al, Am. J. Clin. Nature. 42, 1179-1182. 1982). TNF levels have been measured in patients with cancer and chronic disease associated with cachexia.
  • TNF ⁇ and IL-1 have been implicated in the pathology of other diseases associated with chronic inflammation apart from toxic shock and cancer-related cachexia.
  • TNF has been detected in synovial fluid in patients with both rheumatoid and reactive arthritis and in the serum of patients with rheumatoid arthritis (Saxne et al, 1988. Arthrit. Rheumat. 31, 1041). Raised levels of TNF have been detected in renal transplant patients during acute rejection episodes (Maury and Teppo 1987, J. Exp. Med. 166, 1132).
  • TNF has been shown to be involved in the pathogenesis of graft-versus-host disease in skin and gut following allogenic marrow transplantation.
  • Administration of a rabbit anti-murine TNF antibody was shown to prevent the histological changes associated with graft-versus-host disease and to reduce mortality (Piquet et en, 1987, J. Exp. Med. 166, 1220).
  • TNF has also been shown to contribute significantly to the pathology of malaria (Clark et al, 1987, Am. J. Pathol. 129, 192-199). Further, elevated serum levels of TNF have been reported in malaria patients (Scuderi et al, 1986, Lancet 2, 1364-1365).
  • PUFAs are known to have a range of useful biological activities (see for example International Patent Application Nos. WO 93/00084 and WO 95/00607 and the references cited therein). Unfortunately, due to their limited stability in vivo, PUFAs have not achieved widespread use as therapeutic agents. The present inventors have found that PUFAs including at least one ⁇ oxa, ⁇ thia, ⁇ oxa or ⁇ thia substitution have activity in a number of in vitro systems which suggest that these PUFAs may be useful in treatment of a range of disease states. In addition, the present inventors have developed substituted PUFAs which while retaining biological activity have increased stability in vivo ie slower metabolic turnover. The conjugation of an amino acid to PUFA also increases solubility of the compound.
  • the present inventors have also found that certain of the amino acid coupled PUFA suppress cytokine production and inhibit inflammation in response to carageenan and delayed type hypersensitivity to sheep red blood cells. Such compounds have utility in the treatment of T cell-mediated diseases, autoimmune disease, transplant rejection, graft vs host disease and allergic disease.
  • saturated ⁇ oxa fatty acids can be obtained using the standard procedure for ether synthesis, by reaction of alkyl halides with dianions of ⁇ -hydroxy acids or by treating ⁇ -halo acids with deprotonated alcohols, the unsaturated ⁇ -oxa fatty acids of the present invention are not accessible using normal methods. Attempts to obtain the unsaturated compounds in this manner lead only to decomposition products, resulting from undesirable side reactions at the olefinic and allylic carbons.
  • saturated ⁇ -oxa fatty acids have been obtained through nucleophilic substitution reactions under less vigorous conditions, by treating diazoacetates, activated by complexation with boron trifluoride etherate, with alcohols.
  • boron trifluoride etherate is known to cause isomerization of alkenes and it is therefore unsuitable for use in the synthesis of unsaturated ⁇ -oxa fatty acids.
  • the carbene can be generated from the corresponding diazo acetate or diazo alkane. by treatment with a catalyst such as a rhodium salt.
  • Reaction of the carbene with the complementary alcohol which is either a derivative of ⁇ -hydroxy acetic acid or an unsaturated fatty alcohol affords the unsaturated ⁇ -oxa fatty acid.
  • the alcohols are those obtained by reduction of naturally occurring unsaturated fatty acids or the corresponding exters, and reaction with an ester of diazo acetic acid affords the unsaturated ⁇ -oxa fatty acid.
  • the present invention consists in a method of treating or ameliorating the symptoms of multiple sclerosis in a subject, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a polyunsaturated fatty acid and a pharmaceutically acceptable carrier; in which the polyunsaturated fatty acid contains 18-25 carbons, 1-6 double bonds and has one or two substitutions selected from the group consisting of ⁇ oxa, ⁇ oxa, ⁇ thia and ⁇ thia, or the polyunsaturated fatty acid contains 16-26 carbon chain, 3-6 double bonds and is covalently coupled at the carboxylic acid group to an amino acid.
  • the present invention consists in a method of treating or ameliorating the symptoms of rheumatoid arthritis or other rheumatoid-like condition such as lupus in a subject, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a polyunsaturated fatty acid and a pharmaceutically acceptable carrier; in which the polyunsaturated fatty acid contains 18-25 carbons, 1-6 double bonds and has one or two substitutions selected from the group consisting of ⁇ oxa, ⁇ oxa, ⁇ thia and ⁇ thia, or the polyunsaturated fatty acid contains 16-26 carbon chain. 3-6 double bonds and is covalently coupled at the carboxylic acid group to an amino acid.
  • the present invention consists in a method of treating or ameliorating the symptoms of T-cell mediated disease in a subject, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a polyunsaturated fatty acid and a pharmaceutically acceptable carrier; in which the polyunsaturated fatty acid contains 18-25 carbons, 1-6 double bonds and has one or two substitutions selected from the group consisting of ⁇ oxa, ⁇ oxa, ⁇ thia and ⁇ thia, or the polyunsaturated fatty acid contains 16-26 carbon chain, 3-6 double bonds and is covalently coupled at the carboxylic acid group to an amino acid.
  • T-cell mediated diseases include allergic diseases, such as vasculitis, allergic contact dermatitis and contact derma toconjunctivitis, chronic inflammatory diseases, such as Crohn's disease, inflammatory bowel disease and polymyositis, recurrent inflammatory disease such as herpes simplex stromal keratitis, and transplant rejection, graft vs. host and autoimmune diseases such as scleroderma, rheumatoid arthritis and multiple sclerosis.
  • allergic diseases such as vasculitis, allergic contact dermatitis and contact derma toconjunctivitis
  • chronic inflammatory diseases such as Crohn's disease, inflammatory bowel disease and polymyositis
  • recurrent inflammatory disease such as herpes simplex stromal keratitis
  • transplant rejection graft vs. host
  • autoimmune diseases such as scleroderma, rheumatoid arthritis and multiple sclerosis.
  • the present invention consists in a method of treating or ameliorating the symptoms of a disease state involving elevated levels of products of arachidonic acid metabolism in a subject, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a polyunsaturated fatty acid and a pharmaceutically acceptable carrier; in which the polyunsaturated fatty acid contains 18-25 carbons, 1-6 double bonds and has one or two substitutions selected from the group consisting of ⁇ oxa, ⁇ oxa, ⁇ thia and ⁇ thia, or the polyunsaturated fatty acid contains 16-26 carbon chain, 3-6 double bonds and is covalently coupled at the carboxylic acid group to an amino acid.
  • the polyunsaturated fatty acid is a polyunsaturated fatty acid which contains 18-25 carbons, 1-6 double bonds and has one or two substitutions selected from the group consisting of ⁇ oxa, ⁇ oxa, ⁇ thia and ⁇ thia. It is further preferred that this polyunsaturated fatty acid includes a further substitution selected from the group consisting of hydroxy, hydroperoxy, peroxy and carboxymethyl substitutions.
  • the substituted fatty acid is covalently attached to an amino acid, preferrably glycine or aspartic acid.
  • the polyunsaturated fatty acid has a ⁇ hydroxy substitution.
  • the polyunsaturated fatty acid compound contains 20-25 carbon atoms and 3-6 double bonds and is preferably an n-3 to n-6 fatty acid.
  • the polyunsaturated fatty acid is 21 carbons with 3-4 double bonds containing a ⁇ oxa or ⁇ thia substitution, 22 carbon atoms with 3-4 double bonds containing a ⁇ thia or ⁇ oxa substitution, 23 carbons with 3-4 double bonds containing a ⁇ thia substitution, 24 carbons with atoms with 3-4 double bonds containing a ⁇ thia substitution 25 carbons with 306 double bonds containing a ⁇ oxa substitution, 25 carbons with 3-6 double bonds containing a ⁇ this substitution, or 23 carbons, 3-6 double bonds, ⁇ thia and ⁇ -carb oxy methyl group.
  • the polyunsaturated fatty acid is a polyunsaturated fatty acid which contains 16-26 carbon chain, 3-6 double bonds and is covalently coupled at the carboxylic acid group to an amino acid. It is also preferred that the amino acid is glycine or aspartic acid.
  • the polyunsaturated fatty acid compound is ⁇ -linolenic acid-glycine, ⁇ -linolenic acid-glycine, arachidonic acid-glycine, docosahexaenoic acid-glycine, eicosapentaenoic acid-glycine, ⁇ linolenic acid-aspartic acid, ⁇ -linolenic acid-aspartic acid, arachidonic acid-aspartic acid, eicosapentaenoic acid- aspartic acid or docosahexaenoic acid-aspartic acid.
  • Fig la shows Arachidonic acid 5,8,11,14-Eicosatetraenoic acid.
  • Fig lb shows 5-Hydroperoxy-6E, 8X. IIZ, 14Z-Eicosatetraenoic acid
  • Fig lc shows 9-Hydroperoxy-5Z, 7E, IIZ, T-Eicosatetraenoic acid
  • Fig id shows 8-Hydroperoxy-5Z. 9E, IIZ, acid
  • Fig le shows 12-Hydroperoxy-5Z, 8Z, 10E, 14Z Eicosatetraenoic acid
  • Fig If shows ll-Hydroperoxy-5Z, 8Z, 12E, 14Z Eicosatetraenoic acid.
  • Fig lg shows 15-Hydroperoxy-5Z, 8Z, IIZ, 13E Eicosatetraenoic acid.
  • Fig lh shows 5-Hydroperoxy-6E, 8Z, IIZ, 14Z-Eicosatetraenoic acid.
  • Fig li shows 9-Hydroperoxy-5Z, 7E, IIZ, 14Z Eicosatetraenoic acid.
  • Fig lj shows 8-Hydroperoxy-5Z, 9E, IIZ, 14Z-Eicosatetraenoic acid.
  • Fig Ik shows 12-Hydroperoxy-5Z, 8Z, 10E, 14Z Eicosatetraenoic acid.
  • Fig ll shows ll-Hydroperoxy-5Z, 8Z, 12E, 14Z Eicosatetraenoic acid.
  • Fig lm shows 15-Hydroperoxy-5Z, 8Z, 11ZE. 13E Eicosatetraenoic acid.
  • Fig ln to Fig lz show a range of substituted PUFAs in which Y is hydroxy, hydroperoxy or peroxy.
  • Fig 2a shows ⁇ -oxa 23:4 (n-6)
  • Fig 2b shows ⁇ -oxa 21:3 (n-6)
  • Fig 2c shows ⁇ -oxa 23:4 (n-3)
  • Fig 2d shows ⁇ -oxa 25:6 (n-3)
  • Fig 2e shows ⁇ -oxa 21:4 (n-3)
  • Fig 2f shows ⁇ -thia 23:4 (n-6)
  • Fig 2g shows ⁇ -thia 21:3 (n-6)
  • Fig 2h shows ⁇ -thia 21:3 (n-3)
  • Fig 2i shows ⁇ -thia 25:6 (n-3)
  • Fig 2j shows ⁇ -carboxymethyl- ⁇ -thia 23:4 (n-6)
  • Fig 2k shows ⁇ -thia 24:4 (n-6)
  • Fig 21 shows ⁇ -thia 22:3 (n-6)
  • Fig 2m shows ⁇ -thia 22:3 (n-3)
  • Fig 2n shows 16-OH- ⁇ -oxa 21:3 (n-6)
  • Fig 2o shows 16-OH ⁇ -oxa 23:4 (n-6)
  • Fig 3 shows the effect of novel PUFA 20:4 - aspartic acid, ⁇ oxa 21:3n- 3 and ⁇ carboxymethyl ⁇ thia 23:4n-6 on neutrophil chemiluminescence.
  • Fig 4 shows the effect of ⁇ oxa 21:3n-3 on the arachidonic acid- induced chemiluminescence response.
  • Fig 5 shows the effect of novel PUFA 20:4 - aspartic acid, ⁇ oxa 21:3n-3 and ⁇ carboxymethyl ⁇ thia 23:4n-6 on the delayed type hypersensitivity response induced by sheep red blood cells.
  • Fig 6 shows the effect of 20:4n-6 - aspartic acid on carrageenan- induced paw oedema.
  • Fig 7 shows the effect of ⁇ oxa 21:3 n-3 on carrageenan-induced paw oedema.
  • Mononuclear cells were separated from peripheral blood of normal human donors as described by Ferrante and Thong (1980, J. Immunol.
  • the mononuclear cells were resuspended in RPMI-1640 containing 20% human AB serum and placed into 96 well microtrays (50 ⁇ l per well, cell density 4X10 6 cells/ml). Fatty acid (66 ⁇ m) was then added in 50 ⁇ l and pre-incubated with the cells for 30 min at 37°C in 5% C0 2 . Mitogen (PHA, ConA, PWM, Staph. aureus) was then added in lOO ⁇ l and the cells incubated for 66 hours at 37°C in 5% C0 2 before the addition of tritiated thymidine (l ⁇ Ci/well). After a total of 72h in culture the cells were harvested and proliferation (thymidine incorporation) and supernatant's assayed for the presence of cytokines.
  • Cytokine levels in culture supernatants were determined by specific ELISA using anti-cytokine antibodies. The following cytokine levels were determined TNF ⁇ , TNF ⁇ , interferon- ⁇ , IL-l ⁇ , IL-2.
  • mice Female balb/c mice were administered a priming dose of lOO ⁇ l of a
  • mice 10% haematocrit of sheep red blood cells (SRBC) subcutaneously.
  • mice Six days later mice were administered 25 ⁇ l of a 10% haematocrit of SRBC intradermally into the right hind footpad at time T- Ohrs.
  • the subsequent anti-inflammatory response was evaluated by measuring the thickness of both hind footpads.
  • Standard anti-inflammatory compounds, vehicle and test substances were administered intraperitoneally one hour prior to the SRBC challenge.
  • PUFA compounds were administered in peanut oil. LEUKOTRIENE B4 PRODUCTION IN NEUTROPHILS.
  • mice Female BALB/c mice were administered 25 ⁇ l of a 1% solution of carageenan (Sigma Chemical Company) into the right hind footpad. Test substances were administered ip one hour prior to the administration of carrageenan. The subsequent inflammatory response was evaluated by measuring the thickness of both hind footpads.
  • carageenan Sigma Chemical Company
  • Neutrophils were prepared from the blood of healthy volunteers. Freshly collected blood was layered onto a Hypaque-Ficoll medium of density 1.114 and centrifuged at 400g for 30 minutes at room temperature. After centrifugation the leukocytes resolved into two distinct bands, with neutrophils being present in the second band (Ferrante and Thong, 1982, /. Immunol. Methods. 48:81-85). Activation of neutrophils was measured by lucigenin-dependent chemiluminescence following a 10 minute incubation of test compound (20 ⁇ M final) with 1x10° neutrophils (Kumaratilake et al. 1990. Clin. Exp. Immunol. 80:257-262). CHEMICAL SYNTHESIS
  • Arachidonyl Alcohol (la) - Nu Chek Prep., Elysian, MN, USA Gamma Linolenyl Alcohol (lb) - Nu Chek Prep., Elysian, MN, USA Linolenyl Alcohol (ic) - Nu Chek Prep., Elysina, MN, USA Docosahexaenyl Alcohol (Id) - Nu Chek Prep., Elysian, MN, USA 6, 9, 12, 15-Octadecatetraenyl alcohol (le) - Synthesised by lithium aluminium hydride reduction of Methyl 6, 9, 12, 15-Octadecatetraenoate.
  • the relevant fatty alcohol 1 (1 mol equivalent) was weighed into a two-neck round bottom flask under dry nitrogen and was dissolved in dichloromethane. To this stirred solution was added rhodium acetate dimer (0.5 mol%), followed by the dropwise addition of a solution of tert-butyl diazoacetate 2(2.5 mol equivalents) in dichloromethane via syringe. After the addition was complete the reaction mixture was stirred at toom temperature under nitrogen for 2 hrs.
  • the crude reaction mixture was concentrated under a stream of dry nitrogen and the residue was purified by flash column chromatography on silica, eluting with hexane/diethyl ether (9:1), to afford the relevant terf-butyl alkloxyecetate 3 as an oil.
  • R CH 3 (CH 2 ) 4 (CH ⁇ cis CHCH 2 ) 4 (CH 2 ) 3 .
  • R CH 3 (CH 2 ) 4 (CH cis CHCH 2 ) : ,(CH 2 ) 4 .
  • R CH 3 CH 2 (CH cis CHCH 2 ) 3 (CH 2 ) 7 .
  • R CH 3 CH 2 (CH cis CHCH 2 ) c (CH 2 ) 2 .
  • the resulting extract was concentrated under a stream of dry nitrogen and the residue was purified by flash chromatography on silica, eluting with hexane/diethyl ether/acetic acid (40:60:2) to afford the relevant alkylthioacetic acid 3 as an oil.
  • Alkylthioproprionic acids 5a-c The alkylthioproprionic acids 5a-c were synthesized by alkaline condensation of the respective fatty bromides la-c with mercaptoproprionic acid 4. in an analogous manner to that described above for the alkylthioacetic acids 3a-d.
  • the hydroperoxide derivatives of arachidonic acid are obtained separately from enzyme-catalysed reactions of 1, or as a mixture by autoxidation of la.
  • the components of the autoxidation mixture Figs lb - lg which vary in ratio depending on the reaction conditions, can be separated by high performance liquid chromatography on silica. Reduction of the hydroperoxides Figs lb - lg, either separately or as a mixture affords the corresponding alchohols Figs lh - lm. These can be converted to the corresponding peroxides Fig ln (R-alkyl or aryl).
  • the acid 18 can be prepared by aldol condensation of a corresponding ester of Fig la, while Figs ls - lx are obtained by ether or thioether synthesis, through nucleophilic substitution or metal catalysed coupling reactions, and the thioethers Figs lv - lx can be oxidised to the corresponding sulphoxides and sulphones.
  • the amino acid derivatives Fig ly and Fig lz can be obtained by coupling the corresponding fatty acid Fig la and glycine and aspartic acid respectively.
  • Arachidonic acid (0.50 g) was dissolved in DMF (2.0mL), HOSu (0.38 g om 0.5 mL DMF) and H-Gly-OtBu.HCl (0.55 g in 1.5 mL DMF) were added. The mixture was cooled in an ice bath. DCC (0.41 g in 0,5 mL DMF) was added. N-MM was added and the mixture was stirred for 30 minutes in ice bath and then stireeed at room temperature for 20 hours. The reaction did not go to completion and about 20-3-% arachidonic acid was not reacted.
  • Stepwise increments of %B 10%--20--30-40-50-60-70-80--85- 100%B.
  • Epe-Gly-OtBu coloured oil (0.49 g, 71%).
  • the oil was redissolved in cold trifluoroacetic acid (30 mL) and stirred fro an hour. TFA was evaporated to leave a black oil.
  • the crude Epe-Gly-OH was purified by HPLC to yield 0.13 g (22%) brown oil).
  • H-Asp(OtBu)- OtBu.HCl (0.28 g), HOSu (0.11 g), DCC (0.12 g) and N-MM (0.20 g) were added and the mixture stirred for further 20 hours. About 17% Epe acid remained. The mixture was filtered and the crude Epe-Asp(OtBu)-was purified by HPLC and yielded 0.83 g (94%) brown oil. Cold trifluoroacetic acid (30 mL) was added to the brown oil and the mixture stirred for an hour. TFA was evaporated to leave a dark brown oil which was redissolved in
  • Buffer A 0.1% TFA/H z O
  • Buffer B 0.1% TFA + 10% H 2 O + 90% CH 3 CN 40 mL/min, 214 nm, C18 SemiPrepPak
  • Increments of %B 10%--20--30--40-50--52-55--57-60--65--68-70% Epe acid eluted at 65% B, Epe-Asp(OtBu)-OtBu eluted at 70% B, Epe- Asp-OH eluted at 55% B.
  • Buffer 0.1% TFA + 10% H 2 0 + 90% CH 3 CN 2 mL/min, 214 nm, C18 NovaPak, isocratic Retention times:
  • Epe acid Rt 3.1 min
  • Epe-Asp(OtBu)-OtBu Rt 6.7 min
  • Epe-Asp-OH Rt 1.8 min
  • Buffer A 0.1% TFA/H 2 0 Buffer B: 0.1% TFA + 10% H z O + 90% CH 3 CN
  • H-Asp(OtBu)-OtBu.HCl and HOSu were dissolved together in DMF (2 mL).
  • the mixture was cooled in ice bath and docosahexaenoic acid, DCC (in 0.4 mL DMF), and N-methylmorpholine were added.
  • the mixture stirred in ice bath for 30 minutes and then at room temperature for 4 hours. 30% docosahexaenoic acid (Dhe acid) remained. More DCC (0.11 g) was added and the mixture stirred for further 20 hours. About 18% Dhe acid remained.
  • the mixture was filtered and the crude product was purified by HPLC.
  • the lyophilised Dhe-Asp(OtBu)-OtBu (light yellow oil) weighed 0.73 g (86%).
  • Cold TFA (30 mL) was added to the oil and the mixture stirred for an hour, TFA was evaporated to leave a dark brown oil which was redissolved in CH 3 CN (5 mL) and was purified by HPLC.
  • the purified Dhe-Gly-OH was lyophilised to leave a dark brown oil (0.33 g. 49%).
  • Buffer B 0.1% TFA + 10% H z O + 90% CH 3 CN 40 mL/min, 214 nm, C18 SemiPrepPak manual increment of %B: 10%--20--30--40--50--55--60--65--68-70--73-
  • Buffer B 0.1% TFA + 10% H z O + 90% CH 3 CN 40 mL/min, 214 nm, C18 small prep column Lino-Gly-OH eluted at 65% B, linolenic acid eluted at 67% B, linolenyl-Gly-OtBu eluted also at 67% B but slightly later.
  • Buffer A 0.1%
  • buffer B 0.1% TFA/ 10%H 2 O/90% CH 3 CN 2 mL/min, 214 nm, C18 NovaPak
  • Linolenic acid, HOSu and H-Asp(OtBu)-OtBu.HCl were dissolved together in DMF (3 mL), the mixture cooled in ice bath and DCC (in 0.3 mL DMF) added. N-MM was added and the mixture stirred for 20 hours, after which time some unreacted linolenic acid remained. More DCC (0.10 g) was added and the mixture stirred for further 20 hours. DCU was filtered off and the product isolated by reverse phase HPLC. The purified product was concentrated to an oil (0.66 g) and TFA (30 mL) was added.
  • Buffer A 0.1% TFA
  • buffer B 0.1% TFA/ 10% H 2 O/90% CH 3 CN 2 mL/min, 214 nm, C18 NovaPak
  • Buffer A 0.1% TFA
  • buffer B 0.1% TFA/ 10% H 2 O/90% CH 3 CN 2 mL/min, 214 nm, C18 NovaPak 100%
  • HPLC purification buffer A 0.1% TFA / H 2 O Buffer B: 0.1% TFA + 10% H z O + 90% CH 3 CN
  • Buffer A 0.1% TFA
  • buffer B 0.1% TFA/ 10% H 2 O/90% CH 3 CN 2 mL/min, 214 nm, C18 NovaPak 100%
  • Results are from one experiment performed in duplicate and are representative of 4 experiments.

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